Phase II

van Oosterom, et al., 2001⁶
with followup in: van Oosterom, et al., 2002⁴⁵

400-1000 mg dose escalation Phase I; 800 mg Phase II
[9-13 mo]

40 pts
53 [29-69]
63% M

36 had CD117-positive GIST and 4 had non-GIST STS per 2001 report; 35 had CD117 GIST and 5 had non-GIST STS per 2002 report

Liver metastases 75%

60% previous chemotherapy; 10% previous XRT

Tumor response-RECIST CT/PET

Toxicity- NCI CTC v2.0

GIST

36

53%

47%

11%

At minimum followup of 9-13 mo, 81% of GIST patients were still on imatinib

Non-GIST STS

4

25%

75%

Demetri, 2002⁴⁶
with repeated report in: Dagher 2002⁴³ and followup in: Heinrich, 2003⁴⁷

Randomized between 400 and 600 mg
[minimum 9 mo with median 288 dys; Heinrich, et al., report with 19 mo followup with median 594d]

147 pts
54 [18-83]
57% M

All tumors CD117 positive

100% unresectable or metastatic

90% with recurrence at the time of imatinib therapy

Prior therapies:
 98% Surgery
 51% Chemotherapy
 15% Radiotherapy

Mortality: K-M

Tumor response: MRI/CT RECIST

QOL/PM: (ECOG)

Adverse events: CTC 2.0

All

0%

54%

28%

14%

5%

OS at 76 wks = 85%

Median EFS = 17 mo

400 mg dose (73)

0%

49%

32%

16%

3%

600 mg dose (74)

0%

58%

24%

11%

1%

Verweij, 2003⁴⁸

800 mg
[median followup =13+ mo for GIST pts and 2 mo for non-GIST STS pts]

51 (27 GIST 24 STS)
53 [21-75]
67% M

GIST = CD117 positive

All advanced, unresectable or metastatic

Prior therapies:
 88% surgery
 24% radiotherapy
 71% chemotherapy

Tumor response: RECIST

Time to progression

GIST

27

4%

67%

19%

11%

GIST with 73% DFS at 1 yr

Non-GIST STS

24

0%

0%

29%

NR

Verweij, 2004⁴⁹
with followup in: Zalcberg, 2004⁵⁰ (abstract)

Randomized between Imatinib 400 mg/d vs. Imatinib 800 mg/d (given as 400 mg twice daily)
[median followup 760d]

946

473 @400 mg/d
59 [49-67]
60% M

473@800 mg/d
60 [49-68]
61% M

GIST = CD117 positive

All advanced, unresectable or metastatic

400 mg qd:
 87% surgery
 6% radiotherapy
 33% chemotherapy

800 mg qd:
 83% surgery
 8% radiotherapy
 33% chemotherapy

Progression free survival-KM

Overall survival-KM

Tumor response-CT or MRI RECIST

Toxicity-NCI CTC version 2.0

400 mg/d
(473)

5%

45%

32%

13%

5%

1 yr survival:
 400 mg/d = 85%
 800 mg/d = 85%

2 yr survival:
 400 mg/d = 69%
 800 mg/d = 74%

2 yr PFS:
 400 mg/d = 44%
 800 mg/d = 50% (p = 0.026)

220 of the 473 patients on 400 mg/d have PD and 143 have crossed to 800 mg/d; 26% progression free at 1 year with med TTP 78d compared to 203d prior to crossover; toxicity required dose reduction in 31%; interpretation is that crossover is feasible

800  mg/d
(473)

6%

48%

32%

9%

5%

Casali, 2004⁵¹
(abstract)

Unk dose
[9 mo]

135
65 [unk]
70% M
(129 patients evaluable)

GIST = CD117 positive

All advanced, unresectable or metastatic

Tumor response- RECIST

129

44%
(PR + CR)

PFS > 70%

Phase III

Blay, 2004⁵²
(abstract)

Unk doses

One year of imatinib then randomized between continuous imatinib vs. interruption of imatinib until progression then restart
[6 mo]

159
Age unk
61% M

Advanced GIST expressing a KIT or PDGFRa mutation

Progression free survival

Tumor response

159

10%

42%

36%

6%

6%

Reintroduction of imatinib yielded tumor control in all 5 who progressed

Randomized to continuous
N = 23

0%

Randomized to intermittent
N = 23

21%

Rankin, 2004⁵³ and Patel 2003⁵⁴
(abstracts)

Randomized between Imatinib 400 mg/d vs Imatinib 800 mg/d (given as 400 mg twice daily)
[median 768d, range 70-1029d]

746
Age unk
Gender unk

Metastatic GIST

Progression free survival

Overall survival-KM

Tumor response

400 mg

2 yr survival:
 400 mg/d = 78% (CI 73-82%)
 800 mg/d = 73% (CI 68-77%)

2 yr PFS:
 400 mg/d = 50% (CI 45-55%)
 800 mg/d = 53% (CI 47-58%)

164 patients at 400 mg/d have progressed and 88 164 crossed over to 800 mg/d, with 7% PR and 29% SD after crossover; after crossover, median PPS = 4 mo and median OS = 19 mo